Sacituzumab tirumotecan (Sac-TMT) plus pembrolizumab (Pembro) in participants (Pts) with advanced urothelial carcinoma (UC): Results from phase 2 2870-002/SKB264-II-06 study.

744 Background: There are limited 1L therapy options for cisplatin-ineligible patients with locally advanced or metastatic UC (la/mUC), indicating an unmet need for novel treatment strategies. Sac-TMT (MK-2870/SKB264) is a TROP2-directed ADC with a unique bifunctional linker that maximizes delivery of a novel belotecan-derived topo I inhibitor payload to tumor cells, that has shown promising antitumor activity in several tumor types, including as monotherapy in UC (Ye, D, et al. J Clin Oncol 2025;43[suppl 5]:796). We present efficacy and safety data for cohort B in 1L cisplatin-ineligible pts with la/mUC from the phase 2, open-label 2870-002/SKB264-II-06 study (NCT05642780) evaluating sac-TMT + pembro in pts with select solid tumors. Methods: Eligible pts in cohort B were aged ≥18 y, previously untreated, cisplatin-ineligible with la/mUC. Pts with prior adjuvant or neoadjuvant platinum-based therapy or nivolumab were eligible if they had disease recurrence >12 mo after completing therapy. Pts received sac-TMT 4 or 5 mg/kg IV (non-randomized) on days 1, 15, and 29 of each 42-day cycle + pembro 400 mg IV on day 1 of each 42-day cycle for up to 2 years until PD or unacceptable toxicity. Primary endpoints were safety and ORR per RECIST v1.1 by investigator assessment. Secondary endpoints included DCR, DOR, and PFS by investigator assessment. Results: As of May 21, 2025, 40 pts were treated with sac-TMT (26 pts at 4 mg/kg and 14 pts at sac-TMT 5 mg/kg) + pembro. Median follow-up was 14.5 (range, 11.6–21.8) mo. Median age was 66.5 y, 37 pts (93%) were Asian, and 24 (60%) had upper tract UC. Confirmed ORR was 68%, median DOR was 15.4 mo, and median PFS was 11.2 mo (Table). 39 pts (98%) experienced treatment-related AEs including 23 (58%) with grade 3 or 4 treatment-related AEs. Anemia (15%), decreased neutrophil count (15%), and stomatitis (10%) were the most common (incidence ≥10%) grade 3 or 4 treatment-related AEs. No treatment-related deaths occurred. Conclusions: Sac-TMT + pembro showed promising antitumor activity at both 4 and 5 mg/kg in previously untreated, cisplatin-ineligible pts with la/mUC, with a manageable safety profile consistent with that of the individual treatment components. Further studies are warranted. Clinical trial information: NCT05642780 . Outcome Sac-TMT 4 mg/kg + Pembro 400 mgn = 26 Sac-TMT 5 mg/kg + Pembro 400 mgn = 14 Total N = 40 Confirmed ORR, % (95% CI) 65 (44.3–82.8) 71 (41.9–91.6) 68 (50.9–81.4) DCR, % (95% CI) 89 (69.8–97.6) 86 (57.2–98.2) 88 (73.2–95.8) BOR, n (%) CR 0 (0) 1 (7) 1 (3) PR 17 (65) 9 (64) 26 (65) SD 6 (23) 2 (14) 8 (20) PD 1 (4) 1 (7) 2 (5) No assessment a 2 (8) 1 (7) 3 (8) Median DOR, mo (range) 15.4 (3.6–15.4) NR (2.0–17.7+) b 15.4 (2.0–17.7+) b Median PFS, mo (95% CI) 10.9 (5.7–NE) NR (3.7–NE) 11.2 (5.8–NE) NE, not estimable; NR, not reached. a Includes pts without post-baseline assessment on data cutoff date. b “+” indicates no event by time of last disease assessment.