Efficacy and safety of sacituzumab tirumotecan monotherapy in patients with advanced urothelial carcinoma who progressed on or after prior anti-cancer therapies: Report from the phase 1/2 MK-2870-001 study.
Authors: Ye Dingwei , Jiang Shusuan , Yuan Fang , Zhou Fangjian , Jiang Kui , Zhang Xiaoping , Li XingYa , Seneviratne Lasika C. , Yu Guohua , Zhang Mingjun , Zhang Shuang , Chen Mei , Blumenthal Gideon Michael , Akala Omobolaji Oyekunle , Li Yaling , Jing Dian , Ge Junyou , Shi Yanxia 
Published: February 2025

796

Background:
Sacituzumab tirumotecan (sac-TMT; also known as MK-2870/SKB264) is a TROP2 targeting ADC with a hydrolytically cleavable linker and a topoisomerase I inhibitor payload, KL610023 (average drug-to-antibody ratio, 7.4). In patients (pts) with urothelial carcinoma (UC), treatment with the anti-TROP2 ADC sacituzumab govitecan led to treatment-related grade ≥3 neutropenia in 35% of pts and febrile neutropenia in 10%. Cohort 9 of the MK-2870-001 (KL264-01; NCT04152499) evaluated sac-TMT monotherapy in pts with unresectable, locally advanced/metastatic UC who progressed on or after prior anti-cancer treatments.
Methods:
Eligible pts were ≥18 y, had histologically or cytologically confirmed locally advanced/metastatic UC, and had experienced PD on ≥1 prior line of platinum-based therapy. Platinum ineligible pts were eligible if they received prior anti-PD-(L)1 therapy; prior neoadjuvant/adjuvant therapy was counted as a line of therapy if pts progressed ≤12 mo of last dose. Pts must have ECOG PS of ≤1 and measurable disease by CT/MRI. Pts received sac-TMT 5 mg/kg Q2W until PD, unacceptable toxicity, or withdrawal of consent. Primary objective was ORR per RECIST v1.1 by investigator. Secondary objectives included DOR, PFS, OS, and safety.
Results:
49 pts were treated by data cutoff (Jun 30, 2024) with a minimum follow-up of ≥9 wk (11 pts received sac-TMT as a second-line treatment; 38 received sac-TMT as a third-line or later treatment). Median age was 62 and 61 y, respectively; most pts were Asian (81.8%; 100%). Median follow-up was 9.5 mo (range, 7.5–16.2) and 11.7 mo (range, 7.8–17.4), respectively. By data cutoff, 7 (63.6%) and 29 (76.3%) pts, respectively, had discontinued treatment mostly due to PD (45.5%; 55.3%). Treatment-related grade ≥3 AEs occurred in 29/49 (59.2%) of pts, the most common (≥20%) of which were anemia (38.8%) and decreased neutrophil count (28.6 %). No treatment-related deaths were reported by safety data cutoff (May 21, 2024). Efficacy outcomes are shown in the Table.
Conclusions:
sac-TMT monotherapy had promising antitumor activity in pts with advanced UC who progressed on 1L platinum-based therapy. Clinical trial information:
NCT04152499
.

Outcome
UC 2Lsac-TMT 5 mg/kg (n=11)
UC 3L+sac-TMT 5 mg/kg(n=38)

Confirmed ORR
a
n (%)

5 (45.5)
10 (26.3)

95% CI
16.7–76.6
13.4–43.1

CR n (%)
1 (9.1)
0

PR n (%)
4 (36.4)
10 (26.3)

SD n (%)
3 (27.3)
17 (44.7)

PD n (%)
2 (18.2)
10 (26.3)

Not evaluable n (%)
1 (9.1)
1 (2.6)

Median DOR
b
, months (range)

NE (3.48+ to 13.86+)
NE (2.10 to 14.95+)

Median PFS
b
, months (95% CI)

5.78 (1.68–NE)
5.03 (3.52–7.39)

Median OS
b
, months (95% CI)

NE (2.0–NE)
11.5 (8.9–NE)

NE, not evaluable.

“+” indicates no progressive disease or death as of last disease assessment.

a
Includes all pts as-treated, and percentages are based on number of pts in each subgroup.

b
Based on Kaplan-Meier method for censored data.