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.

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.