Sac-TMT Demonstrates Antitumor Activity, Safety in Urothelial Carcinoma

Findings from the phase 1/2 2870-001/KL264-01 (NCT04152499) study show that sacituzumab tirumotecan (sac-TMT), a novel TROP2-directed antibody-drug conjugate (ADC), yielded antitumor activity in patients with advanced or metastatic urothelial carcinoma (UC).^1,2

Sac-TMT demonstrated encouraging antitumor activity across the entire cohort and in key subgroups. A reduction from baseline in the size of target lesions was observed in 68% of the 47 participants with evaluable measurements.

The confirmed objective response rate (ORR), the primary end point of the trial, was 31% (95% CI, 18%–45%). One patient achieved a complete response, and 14 patients achieved partial responses. The disease control rate (DCR) was 71% (95% CI, 57%–83%). The median time to response was 1.8 months (range, 1.6–5.8). The median duration of response was not reached. The 12-month probability of sustained response was 53%.

The progression-free survival (PFS) was 5.5 months (95% CI, 3.6–7.2), and the 18-month PFS was 26% (95% CI, 15%–40%). The overall survival (OS) was 12.1 months (95% CI, 9.9–15.3), and the 18-month OS was 33% (95% CI, 20%–47%).

The benefit was most pronounced in patients receiving sac-TMT as a second-line treatment. In this patient subgroup (n = 12), the ORR was 50%, the DCR was 75%, the median PFS was 5.8 months, the median OS was not reached, and the 18-month OS rate was 50%.

In patients who received sac-TMT as a third-line or later treatment (n = 37), the ORR was 24%, the DCR was 70%, the median PFS was 4.3 months, the median OS was 11.5 months, and the 18-month OS rate was 28%.

Ye Dingwei, PhD, vice president of Fudan University Shanghai Cancer Center, stated in a news release,³ "Traditional chemotherapy has limited efficacy for advanced or drug-resistant UC. The emergence of precision medicines like ADCs is breaking through treatment bottlenecks for patients with poor response to chemotherapy. We are delighted to observe the encouraging clinical outcomes achieved by the sac-TMT monotherapy regimen, particularly its outstanding efficacy even among heavily pretreated patients. This development injects new momentum into the treatment landscape for advanced UC and offers patients a more precise therapeutic option."

Safety Profile of Sac-TMT

The safety profile of sac-TMT was manageable, with no new safety signals. The median duration of treatment was 4.2 months (range, 0-24.8).¹

Only 1 patient (2%) discontinued treatment due to a treatment-related adverse event (TRAE) of grade 3 anemia. There were no grade 5 (fatal) TRAEs. Treatment-related serious adverse events occurred in 7 participants (14%).

Grade 3/4 TRAEs occurred in 63% of participants (n = 31/49); the most frequent were hematologic toxicities. Specifically, the most common grade 3/4 TRAEs were anemia, decreased neutrophil count, decreased white blood cell count, stomatitis, and decreased platelet count.

No events of febrile neutropenia were observed, a significant finding given that 84% of participants had 1 or more risk factors and 35% experienced grade 3/4 neutropenia. There were no grade ≥3 diarrhea events. This is clinically relevant, as diarrhea combined with neutropenia can lead to fatal complications. No participants received primary prophylactic granulocyte-colony stimulating factor (G-CSF), although 47% received it as a secondary treatment after neutropenia was observed.

Study Design and Patient Characteristics

This trial is a first-in-human, open-label, phase 1/2 study focusing on cohort 9 of the phase 2 dose-expansion part. Patients received sac-TMT at a dose of 5 mg/kg intravenously every 2 weeks. The primary end point was ORR. The secondary end points were duration of response, PFS, OS, and safety. The data cutoff date was February 17, 2025, with a median follow-up of 18.8 months.

The study had a total enrollment of 49 patients who were heavily pretreated with advanced disease. The median age of patients was 61 years (range, 40–76). Of the total patients, 69% were male and 96% were Asian. The majority of patients had an ECOG performance score of 1 (86%). As for prior lines of therapy, 76% received ≥ 2 prior lines and 24% received 1 prior line. All the patients received anti-PD-(L)1 therapy and platinum-based chemotherapy.

Of the total patients, 37% received any prior ADC. Additionally, 69% had a high expression score (H-score >200), and 45% had 2 or 3 adverse risk factors.

Next Steps in Research

The results from cohort 9 of the 2870-001/KL264-01 study demonstrate that sac-TMT monotherapy at 5 mg/kg every 2 weeks provides promising and durable antitumor activity in patients with heavily pretreated advanced or metastatic UC. The 31% confirmed ORR, 5.5-month median PFS, and manageable safety profile are encouraging. The absence of febrile neutropenia and severe diarrhea suggests a favorable safety profile, potentially attributable to the ADC's stable linker chemistry.

While limited by its single-arm design, small sample size, and predominantly Chinese population, the study's findings strongly support the continued development of sac-TMT in this setting. Several global studies are underway to further evaluate sac-TMT in UC, including:

• KEYMAKER-U04 (NCT06483334): Evaluating sac-TMT with enfortumab vedotin (Padcev) ± pembrolizumab (Keytruda).
• SKB264-II-06 (NCT05642780): Evaluating sac-TMT plus pembrolizumab.
• TroFuse-027 (NCT06637423): Evaluating sac-TMT in non–muscle-invasive bladder cancer.

REFERENCES

1.Zhu Y, Jiang S, Shi Y et al. Sacituzumab tirumotecan in participants with advanced or metastatic urothelial carcinoma and disease progression after chemotherapy and immune checkpoint inhibitors. Published online November 20, 2025. Accessed December 2, 2025. Annals of Oncology, Volume 0, Issue 0. doi: 10.1016/j.annonc.2025.11.013.

2.Phase I-II, FIH, TROP2 ADC, advanced unresectable/metastatic solid tumors, refractory to standard therapies (KL264-01) (MK-2870-001). ClinicalTrials.gov. Updated May 20, 2025. Accessed December 2, 2025. https://clinicaltrials.gov/study/NCT04152499

3.The Annals of Oncology publishes results of phase II study of sacituzumab tirumotecan monotherapy for urothelial carcinoma. News release. BioSpace. Published November 28, 2025. Accessed December 2, 2025. https://tinyurl.com/53ma7cuf