Sac-TMT Is Active in Heavily Pretreated Advanced/Metastatic Urothelial Carcinoma

The TROP2-directed antibody-drug conjugate sacituzumab tirumotecan (sac-TMT) displayed promising antitumor activity in patients with heavily pretreated advanced or metastatic urothelial carcinoma, according to data from the phase 1/2 2870-001/KL264-01 study (NCT04152499) published in Annals of Oncology.¹

Preliminary data from 2870-001/KL264-01 demonstrated that patients in cohort 9 who received sac-TMT (n = 49) achieved a confirmed overall response rate (cORR) of 31% (95% CI, 18%-45%), including a complete response (CR) rate of 2%, and the disease control rate (DCR) was 71% (95% CI, 57%-83%). The median duration of response (DOR) was not reached (NR; range, 2.1-22.2+). The median progression-free survival (PFS) was 5.5 months (95% CI, 3.6-7.2) and the median overall survival (OS) was 12.1 months (95% CI, 9.9-15.3). The 18-month PFS and OS rates were 26% and 33%, respectively.

“In this analysis of participants with pretreated locally advanced or metastatic urothelial carcinoma from cohort 9 of the 2870-001/KL264-01 study, encouraging antitumor activity was demonstrated with sac-TMT monotherapy, indicated by a cORR of 31% and a median PFS of 5.5 months in the overall cohort,” Yao Zhu, MD, PhD, chief physician, a professor, the PhD supervisor, and the deputy director of the Department of Urology at Fudan University Shanghai Cancer Center in China, and his coauthors wrote in the publication. “Additionally, safety with sac-TMT was manageable in this population at high risk for complications.”

How was the 2870-001/KL264-01 study designed?

2870-001/KL264-01 was a first-in-human study of sac-TMT in patients with advanced, unresectable/metastatic solid tumors who were refractory to standard therapies.^1,2 The study included patients with triple-negative breast cancer, epithelial ovarian cancer, non–small cell lung cancer, gastric adenocarcinoma/gastroesophageal junction adenocarcinoma, small cell lung cancer, hormone receptor–positive HER2-breast cancer, head and neck squamous cell carcinoma, endometrial carcinoma, urothelial carcinoma, and cervical cancer.² Cohort 9 included patients who were at least 18 years old with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma with measurable disease by CT scan or MRI.¹

Patients in cohort 9 were required to have experienced disease progression on or after one or more lines of platinum-based therapy and a prior anti–PD-(L)1 inhibitor. Those who were ineligible for platinum-based therapy were permitted to enroll if they experienced disease progression on or after treatment with a prior anti–PD-(L)1 inhibitor. Additional eligibility criteria included an ECOG performance status of 0 or 1 and adequate laboratory values.

In cohort 9, patients received intravenous sac-TMT at 5 mg/kg every 2 weeks in 4-week cycles. Treatment continued until disease progression, unacceptable toxicity, participant or physician withdrawal, or death.

The primary end point was ORR per RECIST 1.1 criteria as assessed by the investigator. Secondary end points included investigator-assessed DOR and PFS per RECIST 1.1 criteria, OS, safety, and correlation of TROP2 expression with treatment response.

At baseline, the median age in the overall cohort was 61 years (range, 40-76). Most patients were male (69%), Asian (96%), had an ECOG performance status of 1 (86%), had lower urinary tract disease (51%), had 0 or 1 Bellmunt risk factors (55%), had a TROP2 H-score of over 200 (69%), and received adjuvant/neoadjuvant therapy (53%). The median tumor burden was 62 mm (range, 16-152).

What were the additional data published in Annals of Oncology?

Additional findings from 2870-001/KL264-01 revealed that patients who received 1 prior line of therapy (n = 12) achieved a confirmed ORR of 50% (95% CI, 21%-79%), a DCR of 75% (95% CI, 43%-95%), a CR rate of 8%, and a median DOR that was NR (range, 3.8 months to 22.2+ months). The median PFS and OS values in this subgroup were 5.8 months (95% CI, 1.7-not evaluable [NE]) and NR (95% CI, 2.0 months-NE), respectively. The 18-month PFS and OS rates were 33% and 50%, respectively.

Patients who were treated with 2 or more prior therapies (n = 37) experienced a confirmed ORR of 24% (95% CI, 12%-41%) and a DCR of 70% (95% CI, 53%-84%). The median DOR was NR (range, 2.1-22.0+). The median PFS and OS were 4.3 months (95% CI, 3.5-7.2) and 11.5 months (95% CI, 8.9-13.9) respectively. The 18-month PFS and OS rates were 24% and 28%, respectively.

The median duration on treatment was 4.2 months (range, 0-24.8); all 49 patients experienced an any-grade adverse effect (AE). AEs that were grade 3 or higher (73%), serious (35%), led to treatment discontinuation (10%), and led to death (4%) were all reported. The most common grade 3 or 4 treatment-related AEs included anemia (41%), decreased neutrophil count (35%), decreased white blood cell count (20%), stomatitis (12%), and decreased platelet count (8%). No instances of febrile neutropenia AEs were reported.

“The findings presented here demonstrate the promising antitumor activity of sac-TMT monotherapy at 5 mg/kg every 2 weeks in participants with heavily pretreated locally advanced or metastatic urothelial carcinoma,” Zhu and his coauthors wrote. “In addition, the safety profile of sac-TMT reported here was manageable. Overall, these results support future development of sac-TMT in this population.”

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. Ann Oncol. 2026;37(3):P378-387. 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 April 20, 2026. https://clinicaltrials.gov/study/NCT04152499